多巴胺D<sub>3</sub>受体激动剂BP897治疗小鼠多动秽语综合征的疗效及其可能机制

doi:10.3877/cma.j.issn.1673-5250.2015.03.006

目的

探讨多巴胺D₃受体(DAD₃R)激动剂BP897对小鼠多动秽语综合征(TS)的治疗疗效、有效剂量及其可能的作用机制。

方法

将60只健康雄性ICR小鼠按照随机数字表法随机平均分为6组，各组10只，分别为：模型组、BP897Ⅰ组、BP897Ⅱ组、BP897Ⅲ组、阳性对照组及正常对照组。除正常对照组外，其余5组均建立TS小鼠模型。于实验第8天起逐日予小鼠灌胃：对正常对照组及模型组小鼠分别予以生理盐水0.1 mL灌胃，对阳性对照组予以氟派啶醇0.5 mg/kg灌胃，对BP897Ⅰ组、Ⅱ组及Ⅲ组分别予以BP897 0.3，1.0，3.0 mg/kg灌胃。于造模成功后即刻、灌胃第7天及灌胃第28天，分别采用双盲法对小鼠进行刻板行为评分，各组小鼠在灌胃第28天后，采用酶联免疫吸附测定(ELISA)法检测小鼠脑组织中DAD₃R、多巴胺转运蛋白(DAT)及多巴胺含量，并采用统计学方法比较各组刻板行为评分及DAD₃R、DAT、多巴胺含量差异，分析DAD₃R及DAT分别与多巴胺含量的相关性。各组小鼠体质量等一般情况比较，差异均无统计学意义(P>0.05)。

结果

①灌胃第7天及第28天时，小鼠刻板行为评分比较：BP897Ⅱ组及BP897Ⅲ组分别较模型组小鼠显著降低，BP897Ⅱ组较BP897Ⅰ组显著降低，BP897Ⅲ组较BP897Ⅱ组亦显著降低，且差异均有统计学意义(P<0.05)；而BP897Ⅰ组与模型组比较，BP897Ⅲ组与阳性对照组比较，差异则均无统计学意义(P>0.05)。②灌胃第28天时，小鼠脑组织中DAD₃R，DAT及多巴胺含量比较：模型组较BP897Ⅲ组、阳性对照组及正常对照组均显著降低，BP897Ⅲ组较阳性对照组亦显著降低，且差异均有统计学意义(P<0.05)；而模型组分别与BP897Ⅰ组及BP897Ⅱ组比较，阳性对照组与正常对照组比较，差异则均无统计学意义(P>0.05)。③小鼠脑组织中DAD₃R及DAT含量均与多巴胺含量呈正相关关系(r＝0.765，0.766；均为P<0.001)。

结论

1.0～3.0 mg/kg的BP897对治疗小鼠TS有效，而3.0 mg/kg的BP897能更好控制TS模型的刻板行为，其疗效与氟哌啶醇相当。

关键词: BP897, 多动秽语综合征, 受体，多巴胺D₃, 多巴胺质膜转运蛋白质类, 多巴胺, 小鼠，近交ICR

Objective

To explore curative effect, effective dose and its possible mechanisms of dopamine D₃ receptor (DAD₃R) agonist BP897 in treatment of mice with tourette syndrome(TS).

Methods

According to random number table, random number table method, a total of 60 healthy male ICR mice were average divided into 6 groups(n=10 for each group): model group, BP897Ⅰ, Ⅱ, Ⅲ group, positive control group and normal control group.Except normal control group, the other 5 groups were established mice model of TS.Intragastric administration to mice every day from 8th day of experiment: normal control group and model group with 0.1 mL normal saline ; positive control group with haloperidol 0.5 mg/kg; BP897Ⅰ, Ⅱ, Ⅲ group with BP897 0.3, 1.0, 3.0 mg/kg. Upon successful established TS mice model immediately, 7th and 28th of intragastric administration, stereotyped behavior scores of mice were got in double-blind way.On the 28th day of intragastric administration, DAD₃R, dopamine transporter(DAT) and dopamine contents in mice brain tissues were detected by enzyme-linked immunosorbent assay(ELISA), and use statistical methods to compare differences of stereotyped behavior scores, DAD₃R, DAT and dopamine contents among different groups, and analyze relationship between DAD₃R and dopamine, DAT and dopamine.There were no significant differences among 6 groups in general conditions, such as body weight(P>0.05).

Results

①Comparison of stereotyped behavior scores of mice on 7th day and 28th day of intragastric administration: BP897Ⅱ and Ⅲ group were significantly lower than those in model group, respectively, BP897Ⅱ group were significantly lower than those in BP897Ⅰ group, and BP897Ⅲ group were significantly lower than those in BP897Ⅱ group, too, and the differences were significant(P<0.05); but there were no significant differences between BP897Ⅰand model group, BP897Ⅲ and positive control group(P>0.05). ②Comparison of DAD₃R, DAT and dopamine contents in mice brain tissues on 28th day of intragastric administration: Model group were significantly lower than those in BP897Ⅲ group, positive control group and normal control group, respectively, and in BP897Ⅲ group were significantly lower than those in positive control group, too, and the differences were significant(P<0.05); but there were no significant differences between model group and BP897Ⅰgroup, model group and BP897Ⅱ group, positive control group and normal control group(P>0.05). ③DAD₃R and DAT contents in mice brain tissues were both positively correlated with dopamine content(r=0.765, 0.766; P<0.001).

Conclusions

1.0-3.0 mg/kg dose of BP897 can treat mice with TS effectively, and 3.0 mg/kg dose of BP897 can much better control the stereotyped behavior of mice with TS, which can reach the same curative effect with haloperidol.

Key words: BP897, Tourette syndrome, Receptors, dopamine D₃, Dopamine plasma membrane transport proteins, Dopamine, Mice, inbred ICR

表1 5组小鼠刻板行为评分比较(分，±s)

Table 1 Comparison of stereotyped behavior scores of mice among 5 groups(score，±s)

组别	鼠数	灌胃种类及剂量	刻板行为评分
组别	鼠数	灌胃种类及剂量	建模成功后	灌胃第7天	灌胃第28天
模型组	10	生理盐水0.1 mL	3.27±0.37	3.13±0.65	3.11±0.62
BP897Ⅰ组	10	BP897 0.3 mg/kg	3.03±0.19	2.83±0.23	2.82±0.31
BP897Ⅱ组	10	BP897 1.0 mg/kg	3.10±0.37	2.49±0.19	2.36±0.45
BP897Ⅲ组	10	BP897 3.0 mg/kg	3.14±0.57	2.14±0.20	1.73±0.17
阳性对照组	10	氟哌啶醇0.5 mg/kg	3.20±0.38	2.16±0.33	1.79±0.36
F值	?		0.54	13.87	19.46
P值	?	?	0.710	<0.001	<0.001

表1 5组小鼠刻板行为评分比较(分，±s)

Table 1 Comparison of stereotyped behavior scores of mice among 5 groups(score，±s)

组别	鼠数	灌胃种类及剂量	刻板行为评分
组别	鼠数	灌胃种类及剂量	建模成功后	灌胃第7天	灌胃第28天
模型组	10	生理盐水0.1 mL	3.27±0.37	3.13±0.65	3.11±0.62
BP897Ⅰ组	10	BP897 0.3 mg/kg	3.03±0.19	2.83±0.23	2.82±0.31
BP897Ⅱ组	10	BP897 1.0 mg/kg	3.10±0.37	2.49±0.19	2.36±0.45
BP897Ⅲ组	10	BP897 3.0 mg/kg	3.14±0.57	2.14±0.20	1.73±0.17
阳性对照组	10	氟哌啶醇0.5 mg/kg	3.20±0.38	2.16±0.33	1.79±0.36
F值	?		0.54	13.87	19.46
P值	?	?	0.710	<0.001	<0.001

表2 6组小鼠脑组织中DAD₃R、DAT及多巴胺含量比较(ng/g，±s)

Table 2 Comparison of contents of DAD₃R，DAT and dopamine in the brain of mice among 6 groups(ng/g, ±s)

组别	鼠数	灌胃种类及剂量	小鼠脑组织中含量
组别	鼠数	灌胃种类及剂量	DAD₃R	DAT	多巴胺
模型组	10	生理盐水0.1 mL	153.80±58.20	46.00±15.60	0.18±0.04
BP897Ⅰ组	10	BP897 0.3 mg/kg	144.92±69.24	39.64±19.40	0.17±0.03
BP897Ⅱ组	10	BP897 1.0 mg/kg	164.32±74.60	49.93±17.88	0.20±0.08
BP897Ⅲ组	10	BP897 3.0 mg/kg	275.69±78.18	79.88±21.64	0.31±0.05
阳性对照组	10	氟哌啶醇0.5 mg/kg	364.65±68.06	110.26±16.98	0.43±0.07
正常对照组	10	生理盐水0.1 mL	384.86±78.01	119.67±17.78	0.45±0.07
F值	?	?	317.73	207.45	76.62
P值	?	?	<0.001	<0.001	<0.001

表2 6组小鼠脑组织中DAD₃R、DAT及多巴胺含量比较(ng/g，±s)

Table 2 Comparison of contents of DAD₃R，DAT and dopamine in the brain of mice among 6 groups(ng/g, ±s)

组别	鼠数	灌胃种类及剂量	小鼠脑组织中含量
组别	鼠数	灌胃种类及剂量	DAD₃R	DAT	多巴胺
模型组	10	生理盐水0.1 mL	153.80±58.20	46.00±15.60	0.18±0.04
BP897Ⅰ组	10	BP897 0.3 mg/kg	144.92±69.24	39.64±19.40	0.17±0.03
BP897Ⅱ组	10	BP897 1.0 mg/kg	164.32±74.60	49.93±17.88	0.20±0.08
BP897Ⅲ组	10	BP897 3.0 mg/kg	275.69±78.18	79.88±21.64	0.31±0.05
阳性对照组	10	氟哌啶醇0.5 mg/kg	364.65±68.06	110.26±16.98	0.43±0.07
正常对照组	10	生理盐水0.1 mL	384.86±78.01	119.67±17.78	0.45±0.07
F值	?	?	317.73	207.45	76.62
P值	?	?	<0.001	<0.001	<0.001

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Study on curative effect and possible mechanisms of dopamine D₃ receptor agonist BP897 in treatment of mice with tourette syndrome

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Study on curative effect and possible mechanisms of dopamine D3 receptor agonist BP897 in treatment of mice with tourette syndrome

Study on curative effect and possible mechanisms of dopamine D₃ receptor agonist BP897 in treatment of mice with tourette syndrome